A Pilot Study of Neoadjuvant Therapy With Gemcitabine and Cisplatin in Patients With Resectable or Unresectable Intrahepatic Cholangiocarcinoma

This study is to assess the possibility of using radiation therapy to treat intrahepatic
cholangiocarcinoma. Radiation therapy is used for many other types of malignancies, but its
use for the treatment of this form of gastrointestinal cancer has been limited. This
treatment is still being studied as research doctors are trying to find out more about its
use in the treatment of your form of gastrointestinal cancer. Short course photon radiation
and short course proton beam radiation therapies are FDA (U.S. Food and Drug Administration)
approved radiation delivery systems. This study will also test the safety of neoadjuvant
chemotherapy versus adjuvant chemotherapy. Neoadjuvant therapy is treatment given as a first
step to shrink a tumor before the main treatment, which is usually surgery, is given.
Adjuvant therapy is additional cancer treatment given after the primary treatment to lower
the risk that the cancer will come back.

The current standard of care for patients with intrahepatic cholangiocarcinoma is to offer
surgical resection to all patients who have resectable disease and are able to tolerate a
major surgical intervention.

The study interventions involved this trial may include one or more of the following:

- Chemotherapy (Gemcitabine and Cisplatin)

- Surgical Resection and Lymphadenectomy

- Radiation Therapy

Inclusion Criteria:

- Participants must meet the following criteria on screening examination to be eligible
to participate in the study:

- Participants must have histologically confirmed Intrahepatic Cholangiocarcinoma (IHC)
without evidence of extrahepatic metastasis.

- Participants must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded) as ≥
20 mm with conventional techniques or as ≥10 mm with spiral CT scan.

- Participants with resectable disease must have a single tumor (with no satellite
lesions) with a total diameter or longest dimension of ≤ 20cm. Patients with
unresectable disease must have a total tumor diameter of <20cm and ≤ 3 lesions.
Satellite lesions defined as lesions ≤ 2cm from the dominant lesion are permitted for
participants with unresectable disease

- Patients are not allowed to receive prior surgery or chemotherapy for the IHC.

- Patients with age ≥18 will be included in the study.

- Expected survival must be three months or greater.

- ECOG performance status ≤ 2 (Karnofsky ≥ 70%, see Appendix A).

- Participants must have normal organ and marrow function as defined below:

- Absolute neutrophil count ≥ 1,500/mcL

- Platelets ≥ 100,000/mcL

- Total bilirubin ≤ 2.5 mg/dl

- AST (SGOT)/ALT (SGPT) ≤ 5.0 X institutional upper limit of normal

- Creatinine within normal institutional limits or creatinine clearance ≥ 60
mL/min/1.73 m2 for subjects with creatinine levels above institutional normal .

- No other known active secondary primary malignancy.

- If patient has underlying cirrhosis, only Child-Pugh classification Group A patients
may be included in the resectable cohort of this study. For patients with
unresectable disease, Child-Pugh classification Groups A and B are allowed. Clinical
assessment of ascites and encephalopathy is required. Child-Pugh classification must
be determined for all study participants at the time of eligibility analysis. Note
albumin and PT/INR are required for Child-Pugh classification; these labs should be
drawn with the other labs required for eligibility analysis.

Table 1: Child-Pugh classification of liver function

- Score 1 2 3

- Ascites Absent Slight to moderate Severe

- Encephalopathy Absent Slight to moderate Severe

- Serum albumin >3.5 g/dl 3-3.5 g/dl <3 g/dl

- Serum bilirubin <2 mg/dl 2-3 mg/dl >3 mg/dl

- Prolongation of prothrombin time <4 seconds 4-6 seconds >6 seconds

- Score of 5 to 6 corresponds to Child-Pugh class A

- Score of 7 to 11 corresponds to Child-Pugh class B

- Score of 12 to 15 corresponds to Child-Pugh class

- The effects of gemcitabine+cisplatin on the developing human fetus are unknown. For
this reason, women of child-bearing potential and men must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to
study entry and for the duration of study treatment. Should a woman become pregnant
or suspect she is pregnant while participating in this study, she should inform her
treating physician immediately. Female patients of child bearing potential must
indicate to their physician that they are not pregnant at the time of enrollment or
have a negative serum pregnancy test.

- Ability to understand and the willingness to sign a written informed consent
document.

- Ability to understand and the willingness to sign a written informed consent
document.

Exclusion Criteria:

- Participants who exhibit any of the following conditions at screening will not be
eligible for admission into the study.

- Participants who have had chemotherapy or radiotherapy for intrahepatic
cholangiocarcinoma.

- Participants receiving any other anti-cancer or investigational agents.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to gemcitabine or cisplatin.

- Women who are pregnant or lactating.

- Participants with evidence of non-hepatic metastatic disease.

- Local conditions or systemic illnesses which would reduce the local tolerance to
radiation treatment, such as serious local injuries, active collagen vascular
disease, etc.

- Participants with a serious medical illness which may limit expected survival to less
than 3 months.

- Participants with serious psychiatric illness or social situations which would limit
adherence to study requirements.

- Participants receiving any medications or substances that are strong inhibitors or
inducers of CYP3A4 are ineligible.

- Because no dosing or adverse event data are currently available on the use of
gemcitabine+cisplatin in participants <18 years of age, children are excluded from
this study.

- Patients who require anticoagulation should receive low-molecular weight or standard
heparin and not warfarin.

- Uncontrolled intercurrent illness including, but not limited to ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.

- Pregnant women are excluded from this study because gemcitabine is a class D agent
with the potential for teratogenic or abortifacient effects. Because there is an
unknown but potential risk of adverse events in nursing infants secondary to
treatment of the mother with gemcitabine, breastfeeding should be discontinued if the
mother is treated with gemcitabine. These potential risks may also apply to other
agents used in this study.

- Individuals with a history of a different malignancy are ineligible except for the
following circumstances. Individuals with a history of other malignancies are
eligible if they have been disease-free for at least 5 years and are deemed by the
investigator to be at low risk for recurrence of that malignancy. Individuals with
the following cancers are eligible if diagnosed and treated within the past 5 years:
cervical cancer in situ, DCIS, stage I prostate cancer, and basal cell or squamous
cell carcinoma of the skin.

- HIV-positive individuals on combination antiretroviral therapy are ineligible because
of the potential for pharmacokinetic interactions with gemcitabine+cisplatin. In
addition, these individuals are at increased risk of lethal infections when treated
with marrow-suppressive therapy. Appropriate studies will be undertaken in
participants receiving combination antiretroviral therapy when indicated.
HIV-positive individuals on HAART will be considered eligible of they have
demonstrated good compliance and have a CD4 count > 500.

- Prior liver directed radiation.

- Patients with peripheral neuropathy ≥ grade 2.